{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:23:26Z","timestamp":1791235406347,"version":"4.1.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T00:00:00Z","timestamp":1526428800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T00:00:00Z","timestamp":1526428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterized by vascular lesions, immunological alterations and diffuse fibrosis of the skin and internal organs. Since recent evidence suggests that there is a link between metabolomics and immune mediated disease, serum metabolic profile of SSc patients and healthy controls was investigated by <jats:sup>1<\/jats:sup>H-NMR and GC-MS techniques. The results indicated a lower level of aspartate, alanine, choline, glutamate, and glutarate in SSc patients compared with healthy controls. Moreover, comparing patients affected by limited SSc (lcSSc) and diffuse SSc (dcSSc), 6 discriminant metabolites were identified. The multivariate analysis performed using all the metabolites significantly different revealed glycolysis, gluconeogenesis, energetic pathways, glutamate metabolism, degradation of ketone bodies and pyruvate metabolism as the most important networks. Aspartate, alanine and citrate yielded a high area under receiver-operating characteristic (ROC) curves (AUC of 0.81; CI 0.726\u20130.93) for discriminating SSc patients from controls, whereas ROC curve generated with acetate, fructose, glutamate, glutamine, glycerol and glutarate (AUC of 0.84; CI 0.7\u20130.98) discriminated between lcSSc and dcSSc. These results indicated that serum NMR-based metabolomics profiling method is sensitive and specific enough to distinguish SSc from healthy controls and provided a feasible diagnostic tool for the diagnosis and classification of the disease.<\/jats:p>","DOI":"10.1038\/s41598-018-25992-7","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T09:15:36Z","timestamp":1525943736000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Metabolomic profile of systemic sclerosis patients"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-9851","authenticated-orcid":false,"given":"Federica","family":"Murgia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Svegliati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Poddighe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Lussu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Manzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Spadoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colomba","family":"Fischetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Gabrielli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0606-4959","authenticated-orcid":false,"given":"Luigi","family":"Atzori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,5,16]]},"reference":[{"key":"25992_CR1","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1056\/NEJMra0806188","volume":"360","author":"A Gabrielli","year":"2009","unstructured":"Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N Engl J Med. 360, 1989\u20132003 (2009).","journal-title":"N Engl J Med."},{"key":"25992_CR2","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nrrheum.2010.102","volume":"6","author":"M Trojanowska","year":"2010","unstructured":"Trojanowska, M. Cellular and molecular aspects of vascular dysfunction in systemic sclerosis. Nature Rev Rheumatol. 6, 453\u2013460 (2010).","journal-title":"Nature Rev Rheumatol."},{"key":"25992_CR3","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1002\/art.39084","volume":"67","author":"T Spadoni","year":"2015","unstructured":"Spadoni, T. et al. A Reactive Oxygen Species\u2013mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. Arthritis Rheumatol. 67, 1611\u20131622 (2015).","journal-title":"Arthritis Rheumatol."},{"key":"25992_CR4","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1097\/CCO.0000000000000054","volume":"26","author":"AM Gizinski","year":"2014","unstructured":"Gizinski, A. M. & Fox, D. A. T cell subsets and their role in the pathogenesis of rheumatic disease. Curr Opinion. 26, 204\u2013210 (2014).","journal-title":"Curr Opinion."},{"issue":"6 Suppl 86","key":"25992_CR5","first-page":"S82","volume":"32","author":"M Tauber","year":"2014","unstructured":"Tauber, M. et al. Prevalence and predictors of small intestinal bacterial overgrowth in systemic sclerosis patients with gastrointestinal symptoms. Clin Exp Rheumatol. 32(6 Suppl 86), S82\u201387 (2014).","journal-title":"Clin Exp Rheumatol."},{"key":"25992_CR6","doi-asserted-by":"publisher","first-page":"14874","DOI":"10.1038\/s41598-017-14889-6","volume":"7","author":"V Patrone","year":"2017","unstructured":"Patrone, V. et al. Gut microbiota profile in systemic sclerosis patients with and without clinical evidence of gastrointestinal involvement. Sci Rep. 7, 14874\u201314885 (2017).","journal-title":"Sci Rep."},{"key":"25992_CR7","doi-asserted-by":"publisher","first-page":"595","DOI":"10.2174\/138620712802650522","volume":"15","author":"T Gebregiworgis","year":"2012","unstructured":"Gebregiworgis, T. & Powers, R. Application of NMR, Metabolomics to search for human disease biomarkers. Comb Chem High Throughput Screening. 15, 595\u2013610 (2012).","journal-title":"Comb Chem High Throughput Screening."},{"key":"25992_CR8","doi-asserted-by":"publisher","first-page":"e0151802","DOI":"10.1371\/journal.pone.0151802","volume":"11","author":"YMR Sandlers","year":"2016","unstructured":"Sandlers, Y. M. R. New Mechanisms for Pathogenesis in Barth Syndrome and Introduces Novel Roles for Cardiolipin in Cellular Function. PLoS One. 11, e0151802 (2016).","journal-title":"PLoS One."},{"key":"25992_CR9","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.molonc.2012.10.003","volume":"7","author":"S Weia","year":"2013","unstructured":"Weia, S. et al. Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer. Molecular oncology. 7, 297\u2013307 (2013).","journal-title":"Molecular oncology."},{"key":"25992_CR10","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1517\/17460441003631854","volume":"3","author":"KM Wilcoxen","year":"2010","unstructured":"Wilcoxen, K. M., Uehara, T., Myint, K. T., Sato, Y. & Oda, Y. Practical metabolomics in drug discovery. Expert Opin Drug Discovery. 3, 249\u2013263 (2010).","journal-title":"Expert Opin Drug Discovery."},{"key":"25992_CR11","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.jnutbio.2011.05.016","volume":"22","author":"J McNiven","year":"2011","unstructured":"McNiven, J., German, E. M. S. & Slupsky, J. B. C. M. Analytical metabolomics: nutritional opportunities for personalized health. J Nutr Biochem. 22, 995\u20131002 (2011).","journal-title":"J Nutr Biochem."},{"key":"25992_CR12","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s11306-008-0152-0","volume":"5","author":"JG Bundy","year":"2009","unstructured":"Bundy, J. G., Davey, M. P. & Viant, M. R. Environmental metabolomics: a critical review and future perspectives. Metabolomics. 5, 3\u201321 (2009).","journal-title":"Metabolomics."},{"key":"25992_CR13","doi-asserted-by":"publisher","first-page":"D521","DOI":"10.1093\/nar\/gkl923","volume":"35","author":"DS Wishart","year":"2007","unstructured":"Wishart, D. S. et al. HMDB: the Human Metabolome Database. Nucleic Acids Res. 35, D521\u2013D52 (2007).","journal-title":"Nucleic Acids Res."},{"key":"25992_CR14","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.2217\/14622416.8.9.1243","volume":"9","author":"DI Ellis","year":"2007","unstructured":"Ellis, D. I., Dunn, W. B., Griffin, J. L., Allwood, J. W. & Goodacre, R. Metabolic fingerprinting as a diagnostic tool. Pharmacogenomics. 9, 1243\u20131266 (2007).","journal-title":"Pharmacogenomics."},{"key":"25992_CR15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0014-5793(01)02582-0","volume":"500","author":"JG Bundy","year":"2001","unstructured":"Bundy, J. G., Osborn, D., Weeks, J., Lindon, J. C. & Nicholson, J. K. An NMR-based metabonomic approach to the investigation of coelomic fluid biochemistry in earthworms under toxic stress. FEBS Lett. 500, 31\u201335 (2001).","journal-title":"FEBS Lett."},{"key":"25992_CR16","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1080\/004982599238047","volume":"29","author":"JK Nicholson","year":"1999","unstructured":"Nicholson, J. K., Lindon, J. C. & Holmes, E. \u2018Metabonomics\u2019: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 29, 1181\u20131189 (1999).","journal-title":"Xenobiotica."},{"key":"25992_CR17","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1002\/mas.20108","volume":"26","author":"K Dettmer","year":"2007","unstructured":"Dettmer, K., Aronov, P. A. & Hammock, B. D. Mass spectrometry-based metabolomics. Mass Spectrom Rev. 26, 51\u201378 (2007).","journal-title":"Mass Spectrom Rev."},{"key":"25992_CR18","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1081\/DCT-120014789","volume":"25","author":"NV Reo","year":"2002","unstructured":"Reo, N. V. NMR-based metabolomics. Journal Drug and Chemical Toxicology. 25, 375\u2013382 (2002).","journal-title":"Journal Drug and Chemical Toxicology."},{"key":"25992_CR19","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1586\/14737159.6.5.717","volume":"6","author":"NJ Serkova","year":"2006","unstructured":"Serkova, N. J. & Niemann, C. U. Pattern recognition and biomarker validation using quantitative 1H\u2013NMR-based metabolomics. Expert. Rev. Mol. Diagn. 6, 717\u2013731 (2006).","journal-title":"Expert. Rev. Mol. Diagn."},{"key":"25992_CR20","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1007\/s11095-006-0025-z","volume":"23","author":"JC Lindon","year":"2006","unstructured":"Lindon, J. C., Holmes, E. & Nicholson, J. K. Metabonomics techniques and applications to pharmaceutical research & development. Pharm. Res. 23, 1075\u20131088 (2006).","journal-title":"Pharm. Res."},{"key":"25992_CR21","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/mas.20032","volume":"24","author":"SG Villas-Boas","year":"2005","unstructured":"Villas-Boas, S. G., Mas, S., Akesson, M., Smedsgaard, J. & Nielsen, J. Mass spectrometry in metabolome analysis. Mass Spectrom. Rev. 24, 613\u2013646 (2005).","journal-title":"Mass Spectrom. Rev."},{"key":"25992_CR22","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jchromb.2004.07.045","volume":"817","author":"ID Wilson","year":"2005","unstructured":"Wilson, I. D. et al. HPLC-MS-based methods for the study of metabonomics. J. Chromatog. B Analyt Technol Biomed Life Sci. 817, 67\u201376 (2005).","journal-title":"J. Chromatog. B Analyt Technol Biomed Life Sci."},{"key":"25992_CR23","doi-asserted-by":"publisher","unstructured":"Poddighe, S. et al. Metabolomic analysis identifies altered metabolic pathways in Multiple Sclerosis. International Journal of Biochemistry & Cell Biology; https:\/\/doi.org\/10.1016\/j.biocel.2017.07.004 (2017).","DOI":"10.1016\/j.biocel.2017.07.004"},{"key":"25992_CR24","doi-asserted-by":"publisher","first-page":"e37210","DOI":"10.1371\/journal.pone.0037210","volume":"7","author":"T Wu","year":"2012","unstructured":"Wu, T. et al. Metabolic disturbances associated with systemic lupus erythematosus. PLoS One. 7, e37210 (2012).","journal-title":"PLoS One."},{"key":"25992_CR25","doi-asserted-by":"publisher","first-page":"e44331","DOI":"10.1371\/journal.pone.0044331","volume":"7","author":"HA Van Wietmarschen","year":"2012","unstructured":"Van Wietmarschen, H. A. et al. Characterization of rheumatoid arthritis subtypes using symptom profiles, clinical chemistry and metabolomics measurements. Plos One. 7, e44331 (2012).","journal-title":"Plos One."},{"key":"25992_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-016-0681-8","volume":"14","author":"A Alonso","year":"2016","unstructured":"Alonso, A. et al. Urine metabolome profiling of immune-mediated inflammatory diseases. BMC Med. 14, 133 (2016).","journal-title":"BMC Med."},{"key":"25992_CR27","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.bbagrm.2014.07.013","volume":"1839","author":"V Infantino","year":"2014","unstructured":"Infantino, V., Iacobazzi, V., Menga, A., Avantaggiati, M. L. & Palmieri, F. A key role of the mitochondrial citrate carrier (SLC25A1) in TNF\u03b1- and IFN\u03b3-triggered inflammation. Biochim. Biophys. Acta - Gene Regul. Mech. 1839, 1217\u20131225 (2014).","journal-title":"Biochim. Biophys. Acta - Gene Regul. Mech."},{"key":"25992_CR28","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1515\/hsz-2013-0271","volume":"395","author":"V Iacobazzi","year":"2014","unstructured":"Iacobazzi, V. & Infantino, V. Citrate \u2013 new functions for an old metabolite. Biol Chem. 395, 387\u2013399 (2014).","journal-title":"Biol Chem."},{"key":"25992_CR29","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1177\/0961203311418707","volume":"20","author":"X Ouyang","year":"2011","unstructured":"Ouyang, X., Dai, Y., Wen, J. & Wang, L. X. 1H NMR-based metabolomic study of metabolic profiling for systemic lupus erythematosus. Lupus. 20, 1411\u20131420 (2011).","journal-title":"Lupus."},{"key":"25992_CR30","doi-asserted-by":"publisher","first-page":"3769","DOI":"10.1021\/pr400415a","volume":"12","author":"M Jiang","year":"2013","unstructured":"Jiang, M. et al. Serum Metabolic Signatures of Four Types of Human Arthritis. J. Proteome Res. 12, 3769\u20133779 (2013).","journal-title":"J. Proteome Res."},{"key":"25992_CR31","doi-asserted-by":"publisher","first-page":"e42","DOI":"10.1016\/j.crohns.2012.04.019","volume":"7","author":"NS Stephens","year":"2013","unstructured":"Stephens, N. S. et al. Urinary NMR metabolomic profiles discriminate inflammatory bowel disease from healthy. J Crohn\u2019s Colitis 7, e42\u2013e48 (2013).","journal-title":"J Crohn\u2019s Colitis"},{"key":"25992_CR32","doi-asserted-by":"publisher","first-page":"163","DOI":"10.3748\/wjg.v20.i1.163","volume":"20","author":"T Dawiskiba","year":"2014","unstructured":"Dawiskiba, T. et al. Serum and urine metabolomic fngerprinting in diagnostics of inflammatory bowel diseases. World J Gastroenterol. 20, 163\u2013174 (2014).","journal-title":"World J Gastroenterol."},{"key":"25992_CR33","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1017\/S000711450769936X","volume":"98","author":"P Li","year":"2007","unstructured":"Li, P., Yin, Y., Li, D., Kim, S. W. & Wu, G. Amino acids and immune function. British Journal of Nutrition 98, 237\u2013252 (2007).","journal-title":"British Journal of Nutrition"},{"key":"25992_CR34","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13075-015-0542-4","volume":"17","author":"Z Yang","year":"2015","unstructured":"Yang, Z., Matteson, E. L., Goronzy, J. J. & Weyand, C. T-cell metabolism in autoimmune disease. Arthritis Research & Therapy 17, 29 (2015).","journal-title":"Arthritis Research & Therapy"},{"key":"25992_CR35","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/S0167-5699(00)01593-0","volume":"21","author":"F Buttgereit","year":"2000","unstructured":"Buttgereit, F., Burmester, G. R. & Brand, M. D. Bioenergetics of immune functions: fundamental and therapeutic aspects. Immunol Today. 21, 192\u2013199 (2000).","journal-title":"Immunol Today."},{"key":"25992_CR36","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1111\/j.1365-2796.2010.02218.x","volume":"267","author":"RH Straub","year":"2010","unstructured":"Straub, R. H., Cutolo, M., Buttgereit, F. & Pongratz, G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med. 267, 543\u2013560 (2010).","journal-title":"J Intern Med."},{"key":"25992_CR37","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1101\/sqb.2011.76.010942","volume":"76","author":"Y Xiong","year":"2011","unstructured":"Xiong, Y., Lei, Q. Y., Zhao, S. & Guan, K. L. Regulation of Glycolysis and Gluconeogenesis by Acetylation of PKM and PEPCK. Cold Spring Harb Symp Quant Biol. 76, 285\u2013289 (2011).","journal-title":"Cold Spring Harb Symp Quant Biol."},{"key":"25992_CR38","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1136\/ard.2004.031641","volume":"64","author":"T Gaber","year":"2005","unstructured":"Gaber, T., Dziurla, R., Tripmacher, R., Burmester, G. & Buttgereit, F. Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis. 64, 971\u2013980 (2005).","journal-title":"Ann Rheum Dis."},{"key":"25992_CR39","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.imlet.2010.02.008","volume":"131","author":"R Dziurla","year":"2010","unstructured":"Dziurla, R. et al. Effects of hypoxia and\/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4\u2009+\u2009T lymphocytes. Immunol Lett. 131, 97\u2013105 (2010).","journal-title":"Immunol Lett."},{"key":"25992_CR40","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1186\/ar3885","volume":"14","author":"CM Spies","year":"2012","unstructured":"Spies, C. M., Straub, R. H. & Buttgereit, F. Energy metabolism and rheumatic diseases: from cell to organism. Arthritis Research & Therapy. 14, 216 (2012).","journal-title":"Arthritis Research & Therapy."},{"key":"25992_CR41","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1756-185X.2011.01598.x","volume":"14","author":"X Chang","year":"2011","unstructured":"Chang, X. & Wei, C. Glycolysis and rheumatoid arthritis. Int J Rheum Dis. 14, 217\u2013222 (2011).","journal-title":"Int J Rheum Dis."},{"key":"25992_CR42","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1136\/ard.38.1.63","volume":"38","author":"B Henderson","year":"1979","unstructured":"Henderson, B., Bitensky, L. & Chayen, J. Glycolytic activity in human synovial lining cells in rheumatoid arthritis. Ann Rheum Dis. 38, 63\u201367 (1979).","journal-title":"Ann Rheum Dis."},{"key":"25992_CR43","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/sj.jid.5701107","volume":"128","author":"AS Vincent","year":"2008","unstructured":"Vincent, A. S. et al. Human skin keloid fibroblasts display bioenergetics of cancer cells. J Invest Dermatol. 128, 702\u2013709 (2008).","journal-title":"J Invest Dermatol."},{"key":"25992_CR44","doi-asserted-by":"publisher","first-page":"2140","DOI":"10.4161\/cc.10.13.16227","volume":"10","author":"R Castello-Cros","year":"2011","unstructured":"Castello-Cros, R. et al. Scleroderma-like properties of skin from caveolin-1-deficient mice Implications for new treatment strategies in patients with fibrosis and systemic sclerosis. Cell Cycle. 10, 2140\u20132150 (2011).","journal-title":"Cell Cycle."},{"key":"25992_CR45","doi-asserted-by":"publisher","first-page":"2630","DOI":"10.1161\/CIRCULATIONAHA.105.609008","volume":"113","author":"S Bonnet","year":"2006","unstructured":"Bonnet, S. et al. An abnormal mitochondrial-hypoxia inducible factor-1{alpha}-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation. 113, 2630\u20132641 (2006).","journal-title":"Circulation."},{"key":"25992_CR46","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.2741\/4573","volume":"22","author":"C Wu","year":"2017","unstructured":"Wu, C. et al. The immunological function of GABAergic system. Frontiers In Bioscience 22, 1162\u20131172 (2017).","journal-title":"Frontiers In Bioscience"},{"key":"25992_CR47","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1093\/jn\/134.3.489","volume":"134","author":"G Wu","year":"2004","unstructured":"Wu, G., Fang, Y., Yang, S., Lupton, J. R. & Turner, N. D. Glutathione metabolism and its implications for health. J. Nutr. 134, 489\u2013492 (2004).","journal-title":"J. Nutr."},{"key":"25992_CR48","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/S0955-2863(99)00022-4","volume":"10","author":"P Newsholme","year":"1999","unstructured":"Newsholme, P. et al. Glutamine metabolism by lymphocytes, macrophages, and neutrophils: its importance in health and disease. J Nutr Biochem. 10, 316\u201332 (1999).","journal-title":"J Nutr Biochem."},{"key":"25992_CR49","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.4049\/jimmunol.0903586","volume":"185","author":"EL Carr","year":"2010","unstructured":"Carr, E. L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK\/MAPK during T lymphocyte activation. J Immunol. 185, 1037\u20131044 (2010).","journal-title":"J Immunol."},{"key":"25992_CR50","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/0026-0495(88)90036-4","volume":"37","author":"MS Ardawi","year":"1988","unstructured":"Ardawi, M. S. Glutamine and glucose metabolism in human peripheral lymphocytes. Metabolism. 37, 99\u2013103 (1988).","journal-title":"Metabolism."},{"key":"25992_CR51","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","volume":"72","author":"F Van den Hoogen","year":"2013","unstructured":"Van den Hoogen, F. et al. Classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative. Ann Rheum Dis 72, 1747\u20131755 (2013).","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"25992_CR52","doi-asserted-by":"publisher","first-page":"e185","DOI":"10.1212\/NXI.0000000000000185","volume":"3","author":"E Cocco","year":"2016","unstructured":"Cocco, E. et al. 1H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 3(1), e185 (2016).","journal-title":"Neurol Neuroimmunol Neuroinflamm."},{"key":"25992_CR53","unstructured":"Eriksson, L., Byrne, T., Johansson, E., Trygg, J. & Wikstrom, C. Multi-and Megavariate Data Analysis, Basic principles and applications. Umetrics Academy, Malmo, Sweden. 1\u2013501 (\n                           2013\n                           )."},{"key":"25992_CR54","doi-asserted-by":"publisher","first-page":"4430","DOI":"10.1021\/ac060209g","volume":"78","author":"AM Weljie","year":"2006","unstructured":"Weljie, A. M. et al. Targeted profiling: quantitative analysis of 1H NMR metabolomics data. Anal Chem. 78, 4430\u20134442 (2006).","journal-title":"Anal Chem."},{"key":"25992_CR55","doi-asserted-by":"publisher","first-page":"W251","DOI":"10.1093\/nar\/gkv380","volume":"43","author":"J Xia","year":"2015","unstructured":"Xia, J. et al. MetaboAnalyst 3.0\u2014making metabolomics more meaningful. Nucleic Acids Res. 43, W251\u2013257 (2015).","journal-title":"Nucleic Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-25992-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-25992-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-25992-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T05:20:59Z","timestamp":1671600059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-25992-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,16]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["25992"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-25992-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,16]]},"assertion":[{"value":"29 November 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7626"}}